Cardiometabolic disorders including obesity, insulin resistance, related dyslipidemia, and type 2 diabetes (T2DM) are highly prevalent among U.S. Veterans and serve as major factors in the development of heart, vascular and liver diseases. We have assembled a multi-disciplinary research team from multiple VA and academic medical centers with expertise in cardiovascular and metabolic disease, clinical and epidemiological research, EHR based research methods, genetic epidemiology, and statistical genetics, to participate in the Million Veteran Program (MVP) through the Beta-test award entitled ?Genetics of Cardiometabolic Diseases in the VA Population?. In addition, we have helped establish a highly synergistic network of trait- and methodology-based Working Groups that have facilitated collaborative projects among several funded Beta-test teams. Since first gaining access to MVP genetic and phenotypic data in GenISIS less than 18 months ago, we have contributed substantially to or led studies that have confirmed and/or identified >500 susceptibility loci for body mass index, height, prediabetes, T2D, dyslipidemia, non-alcoholic fatty liver disease (NAFLD), coronary artery disease (CAD), and peripheral artery disease (PAD). We have disseminated our findings to the scientific community through >20 presentations at national meetings and have submitted or are preparing to submit multiple manuscripts related to these initial efforts. For the current renewal application, we propose to continue this line of investigation with particular focus in leveraging longitudinal information related to time course of disease. In Aim 1, we will build on our momentum of our initial genome wide association studies (GWAS) of prevalent disease and single time point measures of quantitative traits by expanding our efforts to examine the genetic basis of the longitudinal progression of cardiometabolic traits including increasing BMI; pre-diabetes to type 2 diabetes, manifestation of micro- and macro-vascular complications in T2D, NAFLD to liver cirrhosis and cancer, pre-clinical conditions to CHD, PAD, and abdominal aortic aneurysm (AAA) disease. In Aim 2, we will explore the pleiotropic relationships between multiple cardiometabolic traits as well as with non-cardiometabolic traits in the MVP and the UK Biobank. Moreover, we will conduct participant-level Mendelian Randomization studies to more robustly document causal links between highly correlated pairs of traits identified through our pleiotropy analyses. Finally, in Aim 3, we will assess the discriminatory power of derived polygenic risk scores for cardiometabolic diseases in the VA population, with specific emphasis upon evaluating their value in different minority populations. Our overarching hypothesis is that elucidating the genetic underpinnings of cardiometabolic conditions and their interactions with environmental and/or lifestyle factors will provide a more precise understanding of disease progression over time, thereby informing more targeted genomic medicine-based disease management throughout the course of Veterans' lives.